Abstract
Transient receptor potential cation channel subfamily M member 4 (TRPM4) has been shown to play a key role in detrusor contractility under physiological conditions. In this study, we investigated the potential role of TRPM4 in detrusor overactivity following spinal cord transection (SCT) in mice. TRPM4 expression and function were evaluated in bladder tissue with or without the mucosa from spinal intact (SI) and SCT female mice (T8-T9 vertebra; 1–28 days post SCT) using PCR, western blot, immunohistochemistry, and muscle strip contractility techniques. TRPM4 was expressed in the urothelium (UT) and detrusor smooth muscle (DSM) and was upregulated after SCT. Expression levels peaked 3–7 days post SCT in both the UT and DSM. Pharmacological block of TRPM4 with the antagonist, 9-Phenanthrol (30 μM) greatly reduced spontaneous phasic activity that developed after SCT, regardless of the presence or absence of the mucosa. Detrusor overactivity following spinal cord injury leads to incontinence and/or renal impairment and represents a major health problem for which current treatments are not satisfactory. Augmented TRPM4 expression in the bladder after chronic SCT supports the hypothesis that TRPM4 channels play a role in DSM overactivity following SCT. Inhibition of TRPM4 may be beneficial for improving detrusor overactivity in SCI.
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We thank Kyoung Kim, Morgan Benner, and Stephany Lynn Daugherty for technical support.
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This work was supported by the following grants: R37 DK54824 to LAB, P01 DK093424 to WCD, LAB and AJK, P30 DK079307 O’Brien Pilot to FAK, R01 DK111382 to WCD, DK114492 and DK106115 to JMB.
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FAK designed and performed experiments, analyzed data, wrote manuscript. JMB, CG, BMcD, AWJ, and AML performed experiments, analyzed data, edited, and approved the manuscript. WCdeG contributed to drafting of the manuscript. IVZ, YI, and LAB edited and approved the manuscript.
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Kullmann, F.A., Beckel, J.M., McDonnell, B. et al. Involvement of TRPM4 in detrusor overactivity following spinal cord transection in mice. Naunyn-Schmiedeberg's Arch Pharmacol 391, 1191–1202 (2018). https://doi.org/10.1007/s00210-018-1542-0
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DOI: https://doi.org/10.1007/s00210-018-1542-0